Cirrhosis represents the liver's response to chronic injury. In the US, the most common causes of cirrhosis include nonalcoholic fatty liver disease (NAFLD), alcohol, and hepatitis C virus infection and it is estimated that over 10 million people have cirrhosis. Many of these patients suffer from debilitating sequela, resulting in decreased quality of life and placing a heavy burden on the healthcare system. The Rockey Laboratory is currently elucidating the mechanisms controlling hepatic fibrosis with the ultimate goal of developing anti- fibrotic therapies to abrogate or reverse cirrhosis in at-risk individuals. Extensive investigation points to the activated hepatic stellate cell (HSC) as the primary cell typ responsible for mediating the fibrogenic response. This cell is also the predominant storage site for vitamin A in the body. However, during liver injury, and the development of fibrosis and cirrhosis, HSCs become activated and lose their vitamin A stores from specialized organelles known as lipid droplets. Retinoic acid (RA), the biochemically active derivative of vitamin A, serves as a mediator of the retinoid signaling cascade, a pathway known to have profibrotic and pro-tumorigenic properties. Further, preliminary data indicate that RA signaling plays an important role on molecular pathways important in TGF signaling, a pathway critically linked to stellate cell activation and fibrogenesis supporting the postulate that depletion of vitamin A from lipid droplets leads to release of RA within the cell, which in turn has critical molecular effectsin the cell. The vitamin A depletion event is termed herein the retinoid burst. The molecular basis for the loss of vitamin A from HSC lipid droplets is also unknown. Given this information, this application proposes the following hypothesis: 1) Liver injury results in RA release from lipid droplets during the retinoid burst causing the activation of HSCs, 2) RA release from lipid droplets leads to lipid droplet depletion seen in activated HSCs, 3) A specific enzyme, retinaldehyde dehydrogenase 1 (RALDH1) is responsible for RA release during the retinoid burst and 4) RA release during the retinoid burst is the trigger for HSC activation and blockade of RA release will maintain HSCs in a quiescent state. The aims of this proposal are to characterize the retinoid burst in activated HSCs, to determine the regulation of and downstream effects of the retinoid burst, and to understand the role of RALDH1 in regulating RA signaling during in vivo liver injury. This research will delineate the retinoid burst in injured HCs and determine the events connecting retinoid metabolism with TGF signaling. All evidence suggests this cascade is potent and a target that can be harnessed for the development of anti-fibrotic agents to abrogate hepatic fibrosis and cirrhosis in at-risk individuals. The training portion of this NRSA proposal is designed to build upon the candidate's research skills and foster her training as a physician-scientist performing high-impact basic research with potential to better patients in need of medical ingenuity. This training plan is the foundation on which the applicant will establish an independent research career in the field of liver fibrosis.